KR101280086B1 - Method for preparing n-phenylpyrazole-1-carboxamides - Google Patents

Abstract

A method of preparing a compound of formula 1 by combining a compound of formula 2 with a compound of formula 3 and sulfonyl chloride is disclosed. Also disclosed are compounds of formula 3 that are useful as starting materials for this method.

Carboxylic acid, anthranilamide, N-phenylpyrazole-1-carboxamide, pyrazolecarboxylic acid

Description

Method for preparing N-phenylpyrazole-1-carboxamide {METHOD FOR PREPARING N-PHENYLPYRAZOLE-1-CARBOXAMIDES}

The present invention relates to a process for coupling carboxylic acid with anthranylamide to produce N-phenylpyrazole-1-carboxamide and to anthranylamide compounds suitable for the process.

PCT Patent Publication No. WO 03/015518 discloses the use of N-acyl anthranilic acid derivatives of formula i as arthropodicide.

Wherein A and B are independently O or S, R ¹ is H, R ² is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkoxycarbonyl or C ₂ -C ₆ alkylcarbonyl R ³ is in particular H or C ₁ -C ₆ alkyl, R ⁴ is especially H or C ₁ -C ₆ alkyl, R ⁵ is H, C ₁ -C ₆ alkyl or halogen, R ⁶ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, CN, C ₁ -C ₄ alkoxy or C ₁ -C ₄ haloalkoxy, R ⁷ is especially a phenyl ring, benzyl ring, five or six member Heteroaromatic ring, naphthyl ring system of which each ring or ring system is optionally substituted with 1 to 3 substituents, and R ⁸ is especially H. This document discloses several methods for preparing compounds of formula (i). However, there is a continuing need for new methods that are lower in cost, more efficient, more practical and easier to handle.

SUMMARY OF THE INVENTION [

The present invention relates to a method for preparing the compound of formula (1).

Wherein,

R ¹ is CH ₃ or Cl,

R ² is Br, Cl, I or CN,

R ³ is H or C ₁ -C ₄ alkyl,

R ⁴ is Cl, Br, CF ₃ , OCF ₂ H or OCH ₂ CF ₃ ,

R ⁵ is F, Cl or Br,

R ⁶ is H, F or Cl,

Z is CR ⁷ or N,

R ⁷ is H, F, Cl or Br.

The method includes combining (1) a carboxylic acid compound of formula (2), (2) aniline compound of formula (3), and 3) sulfonyl chloride to form a compound of formula (1).

The present invention also

R ¹ is CH ³ or Cl,

R ² is Br, Cl, I or CN,

R ³ is H or C ₁ -C ₄ alkyl,

(a) when R ¹ and R ² are Cl, R ³ is other than H, CH ₂ CH ₃ or CH (CH ₃ ) CH ₂ CH ₃ ;

(b) when R ¹ is CH ₃ and R ² is Cl, Br or CN, R ³ is other than CH ₃ or CH (CH ₃ ) ₂ ,

(c) when R ¹ is Cl and R ² is Cl or Br, R ³ is other than CH ₃ or CH (CH ₃ ) ₂ ,

(d) when R ¹ is CH ₃ and R ² is CN, then R ³ is other than H;

It relates to the aniline compound of formula (3).

As used herein, the terms "comprises, includes" "comprising", "including", "has", "having" or any of these Modifications are intended to encompass non-limiting inclusions. For example, a composition, process, method, article, or device comprising any list of components is not necessarily limited to these components alone, but is not explicitly listed or in such a composition, process, method, article, or device It may include other ingredients unique to it. Also, unless stated otherwise, the word "or" is meant to be inclusive or exclusive and not exclusive or meaningful. For example, a condition A or B may be a condition A or B, where A is true (or exists) and B is false (or nonexistent), A is false (or nonexistent) And B are satisfied by any one of the true (or present).

Combining chemicals refers to bringing chemicals into contact with each other.

Also, "negative articles (a and an)" before an element or component of the present invention is not intended to be limited in terms of the number of cases (ie, appearance) of the element or component. Thus, "a" or "an" should be understood to include one or more than one, and the singular forms of elements or components also include the plural unless the number clearly means the singular.

Carbon-based radicals represent monovalent molecular components comprising carbon atoms that connect the radicals to residues of the chemical structure through a single bond. Carbon-based radicals may optionally include saturated, unsaturated and aromatic groups, chains, rings, and ring systems, and heteroatoms. Carbon-based radicals do not have any particular limitation in size, but in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. Of note is a carbon-based radical selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, and phenyl optionally substituted with 1 to 3 substituents selected from C ₁ -C ₃ alkyl, halogen and nitro. .

In the description herein, the abbreviation “Ph” means phenyl. Alkyl may be straight or branched. The term "halogen" in the term itself or in a compound name such as "haloalkyl" includes fluorine, chlorine, bromine or iodine. In addition, when used in compound names such as "haloalkyl", said alkyl may be partially or completely substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" include F ₃ C, ClCH ₂ , CF ₃ CH ₂ and CF ₃ CCl ₂ .

Embodiments of the present invention include the following embodiments.

Embodiment M1. Wherein the molar ratio of compound of formula 2 to compound of formula 3 is from about 1.2: 1 to about 1: 1.2.

Embodiment M2. The method of embodiment M1, wherein the molar ratio of the compound of formula 2 to the compound of formula 3 is about 1: 1 to about 1: 1.2.

Embodiment M3. The method of embodiment M2, wherein the molar ratio of the compound of formula 2 to the compound of formula 3 is about 1: 1.1.

Embodiment M4. Wherein the molar ratio of sulfonyl chloride to compound of formula 2 is at least about 1: 1.

Embodiment M5. The method of embodiment M4, wherein the molar ratio of sulfonyl chloride to compound of formula 2 is about 1: 1 to about 2.5: 1.

Embodiment M6. The method of embodiment M5, wherein the molar ratio of sulfonyl chloride to compound of formula 2 is about 1.1: 1 to about 1.4: 1.

Embodiment M7. The method of embodiment M6, wherein when R ² is Br, Cl or I, the molar ratio of sulfonyl chloride to compound of formula 2 is about 1.2: 1.

Embodiment M8. The method of embodiment M6, wherein when R ² is CN, the molar ratio of sulfonyl chloride to compound of formula 2 is about 1.4: 1.

Embodiment M9. The sulfonyl chloride is a formula (4).

R ⁸ S (O) ₂ Cl

In said formula, R <^8> is a carbon type radical.

Embodiment M10. The phenyl of embodiment M9, wherein R ⁸ is optionally substituted with 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, or halogen, C ₁ -C ₃ alkyl and nitro How to be.

Embodiment M11. The method of embodiment M10, wherein R ⁸ is C ₁ -C ₂ alkyl, CF ₃ , phenyl or 4-methylphenyl.

Embodiment M12. The method of embodiment M11, wherein R ⁸ is C ₁ -C ₂ alkyl, phenyl or 4-methylphenyl.

Embodiment M13. The method of embodiment M12, wherein R ⁸ is CH ₃ .

Embodiment M14. A method of combining carboxylic acid of formula (2), aniline of formula (3) and sulfonyl chloride at a temperature of about -70 to 100 ° C.

Embodiment M15. The method of embodiment M14, wherein the temperature is about -20 to 40 ° C.

Embodiment M16. The method of embodiment M15, wherein the temperature is about -10 to 20 ° C.

Embodiment M17. And combining the carboxylic acid of formula 2 with the aniline of formula 3 to form a mixture, and then combining the mixture with sulfonyl chloride.

Embodiment M18. The method of embodiment M17, wherein the base is combined with the mixture before or after combining with sulfonyl chloride.

Embodiment M19. The method of embodiment M17, wherein the base is combined with a compound of Formula 2 and a compound of Formula 3 before or after combining with sulfonyl chloride to form a mixture.

Embodiment M20. A method of combining a base with a compound of formula 2 and a compound of formula 3 and sulfonyl chloride.

Embodiment M21. The method of any one of embodiments M18 to M20, wherein the amount of base is at least about 2 equivalents to sulfonyl chloride.

Embodiment M22. The method of embodiment M21, wherein the amount of base is at least about 2.1 equivalents to sulfonyl chloride.

Embodiment M23. The method of embodiment M22, wherein the amount of base is about 2.1 to 2.2 equivalents relative to sulfonyl chloride.

Embodiment M24. The method of any one of embodiments M18-M20, wherein the base is selected from tertiary amines (including optionally substituted pyridine).

Embodiment M25. The method of embodiment M24, wherein the base is selected from optionally substituted pyridine and mixtures thereof.

Embodiment M26. The method of embodiment M25, wherein the base is selected from 2-picoline, 3-picoline, 2,6-lutidine, pyridine and mixtures thereof.

Embodiment M27. The method of embodiment M26, wherein the base is 3-picolin.

Embodiment M28. A method of combining a solvent with a compound of formula 2, a compound of formula 3, and sulfonyl chloride.

Embodiment M29. The method of embodiment M17, wherein the solvent is combined with the compound of formula 2 and the compound of formula 3 to form a mixture prior to combining with sulfonyl chloride.

Embodiment M30. For embodiments M28 or M29, the solvent is nitrile (eg acetonitrile, propionitrile), ester (eg methyl acetate, ethyl acetate, butyl acetate), ketone (eg acetone, methyl ethyl ketone, methyl Butyl ketone, haloalkanes (eg dichloromethane, trichloromethane), ethers (eg ethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (eg benzene, toluene , Chlorobenzene, dichlorobenzene), tertiary amines (eg trialkylamine, dialkylaniline, optionally substituted pyridine), and mixtures thereof.

Embodiment M31. The method of embodiment M30, wherein the solvent is selected from tertiary amines (eg, trialkylamines, dialkylanilines, optionally substituted pyridine) and mixtures thereof.

Embodiment M32. In embodiment M30, the solvent is nitrile (eg acetonitrile, propionitrile), ester (eg methyl acetate, ethyl acetate, butyl acetate), ketone (eg acetone, methyl ethyl ketone, Methyl butyl ketone, haloalkanes (eg dichloromethane, trichloromethane), ethers (eg ethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (eg , Benzene, toluene, chlorobenzene, dichlorobenzene), and mixtures thereof.

Embodiment M33. The method of embodiment M32, wherein the solvent is acetonitrile.

Embodiment C1. A compound of formula 3 wherein R ¹ is CH ₃ .

Embodiment C2. A compound of formula 3, wherein R ² is Br or Cl.

Embodiment C3. A compound of formula 3 wherein R ² is I.

Embodiment C4. A compound of formula 3, wherein R ² is CN.

Embodiment C5. A compound of formula 3 wherein R ³ is H or CH ₃ .

Embodiment C6. A compound of formula 3 wherein R ³ is CH ₃ .

R ¹ is CH ₃ , R ² is Cl, R ³ is H, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ( Of note is the compound of formula 3, which is CH ₃ ) CH ₂ CH ₃ or C (CH ₃ ) ₃ . R ¹ is CH ₃ , R ² is Br, R ³ is H, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH Of note is a compound of formula 3, wherein (CH ₃ ) CH ₂ CH ₃ or C (CH ₃ ) ₃ . R ¹ is CH ₃ , R ² is I, R ³ is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , Of note is the compound of formula 3, which is CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ or C (CH ₃ ) ₃ . R ¹ is CH ₃ , R ² is CN, R ³ is CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH _Of note is a compound of formula 3, which is ₃ ) CH ₂ CH ₃ or C (CH ₃ ). In addition, and R ₁ is Cl, and R ² is Cl, R ³ is _{CH 2 CH 2 CH 3, CH} 2 CH 2 CH 2 CH 3, CH 2 CH (CH 3) 2 or C (CH _{3) 3} of formula (3) Of note is the compound. R ¹ is Cl, R ² is Br, R ³ is H, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH (CH _Of note is a compound of formula 3, which is ₃ ) CH ₂ CH ₃ or C (CH ₃ ) ₃ . R ¹ is Cl, R ² is I, R ³ is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ Of note is the compound of formula 3, which is CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ or C (CH ₃ ) ₃ . R ¹ is Cl, R ² is CN, R ³ is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ CH ₃ , CH ₂ Of note is the compound of formula 3, which is CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ or C (CH ₃ ) ₃ .

In the following schemes, unless otherwise indicated, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ in compounds of Formula 1 to compounds of Formula 34 are defined in the Summary of the Invention and Description of Embodiments. As shown.

As shown in Scheme 1, the present invention typically provides a compound of Formula 1 by coupling a carboxylic acid of Formula 2 with anthranylamide of Formula 3 using sulfonyl chloride in the presence of a base and a solvent. It is about how to.

Thus, in the process of the invention, the pyrazolecarboxylic acid of formula (2), aniline of formula (3) and sulfonyl chloride are combined (ie contacted) to correspond to the corresponding N-phenyl-pyrazole-1-carboxamide of formula (1). To provide.

While a wide range of reactant ratios is possible, the nominal molar ratio of the compound of Formula 3 to the compound of Formula 2 is typically about 0.9 to 1.1, with about 1.0 being preferred so that all compounds can be consumed completely. The process of the present invention can be carried out over a wide range of temperatures, but is typically carried out in a temperature range of -70 ° C to + 100 ° C. Of note is a temperature of -20 ° C to + 40 ° C. Of particular note is a temperature of -10 ° C to + 20 ° C for reasons of convenient operation, advantageous reaction speed and selectivity, and high process yield.

In order to facilitate coupling of the carboxylic acid and anthranylamide, sulfonyl chloride compounds are used as reactants to form N-phenylpyrazole-1-carboxamide. The nominal molar ratio of sulfonyl chloride to compound of formula (2) is typically from about 1.0 to 2.5, preferably about 1.1 if the cyclization side reaction described below occurs no greater than a small amount (i.e. 0 to 10%). To 1.4. Sulfonyl chloride is typically of the formula R ⁸ S (O) ₂ Cl (Formula 4), wherein R ⁸ is a carbon-based radical. For the purposes of the present invention typically R ⁸ is C ₁ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, or phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl and nitro to be. Since commercially available sulfonyl chloride compounds for the present invention include methanesulfonyl chloride (R ⁸ is CH ₃ ), propanesulfonyl chloride (R ⁸ is (CH ₂ ) ₂ CH ₃ ), benzenesulfonyl chloride (R ⁸ is Ph), and p-toluenesulfonyl chloride (R ⁸ is 4-CH ₃ -Ph). Methanesulfonyl chloride is more preferred because it is cheaper and / or easier to add and / or easier to waste.

In the process of the invention, sulfonyl chloride is combined with pyrazolecarboxylic acid of formula (2) and aniline of formula (3). The reactants may be combined in various orders, for example, sulfonyl chloride with the carboxylic acid of Formula 2 to form a mixture, and then in combination with the aniline of Formula 3. However, in order to prepare certain N-phenylpyrazole-1-carboxamides of formula (1), the most preferred formulation sequence is to combine the carboxylic acid of formula (2) with aniline of formula (3) to form a mixture, followed by sulfonyl chloride It was found that compounding with the mixture includes, for example, adding sulfonyl chloride to a mixture of a compound of formula 2 and a compound of formula 3, because this order of addition This is because it enables convenient control. The reaction rate can be easily controlled by simply controlling the addition rate of the sulfonyl chloride compound. A notable embodiment of the inventive process thus comprises (1) combining the carboxylic acid of formula (2) with aniline of formula (3) to form a mixture, and (2) subsequently combining the mixture with sulfonyl chloride. do. The addition of sulfonyl chloride to a mixture containing aniline of formula (2) can potentially cause undesirable side reactions, but certain stereoelectron profiles of compounds of formula (2) and compounds of formula (3) are significant using the method of the present invention. It was found to facilitate the obtaining of the compound of formula 1 in a high yield.

Compounds of formula 1 are formed when the starting compounds of formula 2 and starting compounds of formula 3 and sulfonyl chlorides are contacted with each other in a combined liquid phase, each of which is at least partially soluble. In particular, since the starting material of formula (2) and the starting material of formula (3) are typically solids at normal ambient temperatures, the process is most satisfactorily carried out using solvents in which the starting compounds are highly soluble. Thus typically the process is carried out in a liquid phase comprising a solvent. In some cases the carboxylic acid of formula (2) may be only slightly soluble, but salts of the carboxylic acid with added base may be more soluble in the solvent. Suitable solvents for this method include nitriles such as acetonitrile and propionitrile, esters such as methyl acetate, ethyl acetate, and butyl acetate, ketones such as acetone, methyl ethyl ketone (MEK), and methyl Butyl ketones, haloalkanes such as dichloromethane and trichloromethane, ethers such as ethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), and p-dioxane, aromatic hydrocarbons such as benzene , Toluene, chlorobenzene, and dichlorobenzene, tertiary amines such as trialkylamine, dialkylaniline, and optionally substituted pyridine, and mixtures thereof. Notable solvents include acetonitrile, propionitrile, ethyl acetate, acetone, MEK, dichloromethane, methyl tert-butyl ether, THF, p-dioxane, toluene, and chlorobenzene. Acetonitrile is particularly notable as a solvent because it usually gives a good product in yield and / or purity.

The reaction is most satisfactorily carried out in the presence of at least one added base since the reaction of the process of the invention produces hydrogen chloride as a by-product and which binds to the basic center in the compounds of formulas (1), (2) and (3). The base may also facilitate the structural interaction of the sulfonyl chloride compound and anthranylamide with the carboxylic acid. The reaction of the added base with the carboxylic acid of formula (2) forms a salt, which may be more soluble than the carboxylic acid in the reaction medium. Bases can be added simultaneously, in turn, or immediately after the addition of sulfonyl chloride, but the base is typically added before the addition of sulfonyl chloride. Some solvents, for example tertiary amines, also act as bases and when used as solvents they will be present in much excess than stoichiometric amounts as bases. If no base is used as solvent, the nominal molar ratio of charged base to charged sulfonyl chloride is typically about 2.0 to 2.2, preferably about 2.1 to 2.2. Preferred bases are tertiary amines including substituted pyridine. More preferred bases include 2-picoline, 3-picoline, 2,6-lutidine, and pyridine. 3-picoline is particularly notable as a base because the salts of carboxylic acid of formula 2 and 3-picolin are usually highly soluble in a solvent such as acetonitrile.

A feature of the process of the present invention is that the N-phenyl of formula 1 is limited while limiting the amount of carboxylic acid, sulfonyl chloride and anthranylamide consumed during the formation of N-phenylpyrazole-1-carboxamide. Allows pyrazole-1-carboxamides to be produced efficiently. The method of the present invention provides a method with less steps and a simpler process than the known methods for the convenient control of the coupling method and for the preparation of N-phenylpyrazole-1-carboxamides such as formula (1).

Preferred embodiments of the present invention combine the pyrazolecarboxylic acid of formula (2), anthranilic acid of formula (3), and a suitable base in a suitable solvent, followed by addition of a sulfonyl chloride compound (alone or in combination with a suitable solvent). It is.

The N-phenylpyrazole-1-carboxamide product of Formula 1 may be separated from the reaction mixture by methods known to those skilled in the art, including crystallization, filtration and extraction. As shown in Scheme 2, in some cases amide 1 is partially cyclized to the iminobenzoxazine of the formula cyclo-1 under coupling reaction conditions.

In this case, it is often advantageous to convert the compound of formula cyclo-1 back to the amide of formula 1 before separating the reaction product. This conversion can be accomplished by treating the reaction mixture with aqueous acid. Alternatively, the mixture of the iminobenzoxazine of formula (cyclo-1) and the amide of formula (1) is isolated and then treated with an amide of formula (1), for example by treatment with dilute aqueous acid, in the presence of a suitable organic solvent. You can switch.

Under the preferred conditions of this process, cyclization side reactions which convert the desired product of formula (1) to a compound of formula (cyclo-1) generally occur only in small amounts, in which case the preferred ratio of sulfonyl chloride and base is such that It is enough to complete. However, some pyrazolecarboxylic acids of Formula 2, anthranilic acid of Formula 3 (eg when R ² is CN) and reaction conditions (eg, sterically hindered substitutions such as 2,6-lutidine as base) In the case of using pyridine), the conversion of the desired product of formula 1 to the formula cyclo-1 compound may occur in a greater amount or may be a dominant reaction. In such cases, the use of sulfonyl chloride and base in high proportions may facilitate the completion of the coupling reaction. Cyclic side reactions stoichiometrically consume an equivalent of sulfonyl chloride in addition to the equivalent of sulfonyl chloride consumed in the coupling reaction. Thus, to generate 100% cyclization, it is stoichiometrically required that the molar ratio of sulfonyl chloride to the compound of formula 2 is 2: 1 in order to achieve complete consumption of the starting material, and typically the molar ratio is about 2.5: A molar ratio of about 1.4: is used when using sulfonyl chloride of less than 1 to a compound of formula (2), in comparison to which cyclization occurs at only 5-10% (typical for most bases when R ² is CN). A molar ratio of about 1.2 is used when sulfonyl chloride of 1 to the compound of formula 2 occurs and occurs to the extent that cyclization side reactions are neglected (typical for most bases where R ² is Br, Cl or I). Sulfonyl chloride is used as the compound of formula (2). If a cyclization reaction is observed, additional amounts of sulfonyl chloride and base can be added during the reaction.

The above describes the valuable features of the process of the invention, which can add at any time an additional amount of any component of the process as needed to complete the conversion. Another example of this valuable feature relates to the situation in which components of formula (2) or components of formula (3) have been inadvertently inadequately charged to the reaction mixture. Such insufficient filling can be detected by analyzing the reaction mixture using any of a variety of commonly known and available methods, including HPLC and NMR. If this is detected, insufficient filling can be corrected by adding more suitable ingredients to the reaction mixture. This can be particularly useful for large scale operations because it recovers from charging errors and prevents the production of expensive intermediates that may occur.

Pyrazolecarboxylic acids of Formula 2 are described in Rodd's Chemistry of Chemistry of Carbon Compounds, Vol. IVa to IVl, S. Coffey editor, Elsevier Scientific Publishing, New York, 1973, Comprehensive Heterocyclic Chemistry, Vol. 1-7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984, Comprehensive Heterocyclic Chemistry II, Vol. 1-9, AR Katritzky, CW Rees, and EF Scriven editors, Pergamon Press, New York, 1996, and serial publications The Chemistry of Heterocyclic Compounds, EC Taylor, editor, Wiley, New York. Prepared by using a heterocyclic synthesis method. Various heterocyclic acids (including pyrazolecarboxylic acids) and general methods for their synthesis are found in PCT Patent Publication No. WO 98/57397.

One procedure particularly useful for preparing pyrazolecarboxylic acids of Formula 2a is shown in Scheme 3 below.

The reaction of pyrazole of formula 6 with 2-halopyridine of formula 7 yields in good yield 1-pyridinylpyrazole of formula 8 with good specificity for the desired positional chemistry. The compound of formula 8 is metallized with lithium diisopropylamide (LDA) and then quenched with lithium carbon dioxide to yield the 1- (2-pyridinyl) pyrazolecarboxylic acid of formula 2a. See PCT Patent Publication No. WO 03/015519 as the main reference for this method.

As shown in Scheme 4, a 3 + 2 cycloaddition of an appropriately substituted iminohalide of Formula 9 with a substituted propiolate of Formula 10 or an acrylate of Formula 11 to form a pyrazolecarboxylic acid of Formula 2b It can manufacture.

Cycloaddition with acrylates requires further oxidation of the intermediate pyrazoline to pyrazole. Hydrolysis of the ester of formula 12 yields a pyrazolecarboxylic acid of formula 2b. Preferred iminohalides for this reaction include trifluoromethyl iminochloride of formula 9a and iminodibromide of formula 9b. Compounds such as Formula 9a are described in J. Heterocycl. Chem. 1985, 22 (2), 565-8). Other compounds of formula 9, such as formula 9b, are obtainable by known methods (Tetrahedron Letters 1999, 40, 2605).

Another method for preparing the pyrazolecarboxylic acid of Formula 2b is shown in Scheme 5 below.

Pyrazoles of formula 13 are described in Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729 using aryl iodine, or methods described in [P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944 can be used to condense with aryl boronic acid using the method as described. The resulting adduct of formula 15 can be oxidized with an oxidizing agent such as potassium permanganate to yield the pyrazolecarboxylic acid of formula 2b.

Starting pyrazoles of formulas (6) and (13) are known compounds or can be prepared according to known methods. For example, pyrazoles of formula 6a (compounds of formula 6 wherein R ⁴ is CF ₃ ) can be prepared by literature procedures (J. Fluorine Chem. 1991, 55 (1), 61-70). Pyrazoles of formula 6b (compounds of formula 6 wherein R ⁴ is Cl or Br) are described in Chem. Ber. 1966, 99 (10), 3350-7.

A useful alternative method for preparing the compound of formula 6b is shown in Scheme 6 below.

The sulfamoylpyrazole of formula (16) is metalized with n-butyllithium followed by anion to hexachloroethane (if R ⁴ is Cl) or 1,2-dibromotetrachloroethane (if R ⁴ is Br) Direct halogenation yields a halogenated derivative of Formula 17a. Clear removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature yields pyrazole of formula 6c in good yield. Those skilled in the art will recognize that the compound of formula 6c is a tautomer of the compound of formula 6b.

In addition, pyrazole carboxylic acid 2 may be prepared by oxidizing pyrazoline of formula 18 to obtain pyrazole of formula 19, and then hydrolyzing with carboxylic acid as shown in Scheme 7 below.

The oxidizing agent may be hydrogen peroxide, organic peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (eg Oxone®), or potassium permanganate. This oxidation reaction is a solvent, preferably Ethers such as tetrahydrofuran, and p-dioxane and the like, organic esters such as ethyl acetate, and dimethyl carbonate and the like, or polar aprotic organics such as N, N-dimethylformamide, and It may be carried out in the presence of acetonitrile and the like.

Halopyrazoline of formula (18) wherein R ⁴ is Cl or Br can be prepared from pyrazolone of formula (20) by treatment with a suitable halogenation reagent as shown in Scheme 8 below.

Halogenation reagents that can be used include phosphorus oxyhalide, phosphorus trihalide, phosphorous pentahalide, thionyl chloride, dihalotrialkylphosphoran, dihalotriphenylphosphoran, oxalyl chloride and phosgene. Preference is given to phosphorus oxyhalides and phosphorus pentahalides. Typical solvents for such halogenation include halogenated alkanes such as dichloromethane, chloroform, and chlorobutane, aromatic solvents such as benzene, xylene, and chlorobenzene, ethers such as tetrahydrofuran, p-di Oxane, diethyl ether, and the like and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. Optionally, organic bases such as triethylamine, pyridine, or N, N-dimethylaniline can be added. The addition of a catalyst, for example N, N-dimethylformamide, is also optional.

Alternatively, a compound of formula 18 wherein R ⁴ is halogen may be a halogen having a different R ⁴ (eg, Cl to prepare a compound of formula 18 wherein R ⁴ is Br) or a sulfonate group such as methanesulfonate, Corresponding compounds of formula 18, which are benzenesulfonates or p-toluenesulfonates, can be prepared by treatment with hydrogen bromide or hydrogen chloride, respectively. By this method, the halogen or sulfonate substituent R ⁴ in the starting material of Formula 18 is replaced with Br or Cl from hydrogen bromide or hydrogen chloride, respectively. Starting compounds of formula 18, wherein R ⁴ is Cl or Br, can be prepared from the corresponding compounds of formula 20 as already described. Starting compounds of formula (18), wherein R ⁴ is a sulfonate group, are used in standard methods, for example, in a suitable solvent such as dichloromethane, for example sulfonyl chloride (e.g. methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride And similarly prepared from the corresponding compounds of formula 20 by treatment with bases such as tertiary amines (eg triethylamine).

Pyrazolecarboxylic acids of formula (2c) wherein R ⁴ is OCHF ₂ or OCH ₂ CF ₃ may be prepared by the method shown in Scheme 9 below.

In this method, instead of the halogenation shown in Scheme 8, the compound of formula 20 is oxidized to the compound of formula 21. The reaction conditions for this oxidation are as described previously for converting the compound of formula 18 to the compound of formula 19 in Scheme 7. The compound of formula 21 may then be alkylated by contacting difluorocarbene prepared in situ from CHClF _{2 in} the presence of a base to form a compound of formula 22. The compound of formula 21 may also be alkylated by contacting CF ₃ CH ₂ Lg, an alkylation reagent, in the presence of a base to form a compound of formula 24. The alkylation reaction is generally carried out in solvents which may include ethers such as tetrahydrofuran or dioxane and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. The base may be selected from inorganic bases such as potassium carbonate, sodium hydroxide or sodium hydride. Preferably the reaction is carried out using potassium carbonate and N, N-dimethylformamide or acetonitrile as solvent. In the alkylation reagent CF ₃ CH ₂ Lg, Lg is a nucleofuge (ie, leaving group), for example halogen (eg Br, I), OS (O) ₂ CH ₃ (methanesulfonate), OS (O) ₂ CF ₃ , OS (O) ₂ Ph-p-CH ₃ (p-toluenesulfonate), and the like. The product of formula 22 can be separated by conventional techniques, for example by extraction. The ester can then be converted to the carboxylic acid of formula 2c by the method already described in order to convert the compound of formula 12 to the compound of formula 2b in Scheme 4.

Compounds of formula 20 may be prepared from compounds of formula 25 as shown in Scheme 10.

In this method, the hydrazine compound of formula 25 is contacted with a compound of formula 26 (which may use fumarate ester or maleate ester or mixtures thereof) in the presence of a base and a solvent. Bases are typically metal alkoxide salts such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide and the like. Polar protic and polar aprotic organic solvents such as alcohols, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like can be used. Preferred solvents are alcohols such as methanol and ethanol. Particular preference is given to those in which the alcohols correspond to fumarate or maleate esters and alkoxide bases (ie the same as what constitutes them). Depending on the reaction conditions and separation means, the -CO ₂ R functional group in the compound of formula 20 can be hydrolyzed to -CO ₂ H, for example the presence of water in the reaction mixture can promote this hydrolysis. Once the carboxylic acid (-CO ₂ H) is formed, it can be converted back to -CO ₂ R where R is C ₁ -C ₄ alkyl using esterification methods known in the art. The desired product The compound of formula 20 can be separated by methods known to those skilled in the art, for example by crystallization, extraction or distillation.

Another aspect of the invention relates to the anthranylamide of formula 3, which is an important intermediate in the process of the invention. Samples of anthraninilamides of Formula 3 are also useful as analytical standards for determining the presence of anthraninilamides.

Anthranylamides of Formula 3 are described, for example, in L. In H. Sternbach et al., J. Org. Chem. 1971, 36, 777-781 can be prepared from the reaction of isatoic anhydride of formula 27 with ammonia or alkylamine as shown in Scheme 11 below.

Istonic anhydride of formula 27 may be prepared by a variety of known methods which are well described in the chemical literature. For example, istonic anhydride is obtainable from the corresponding anthranilic acid via a cyclization reaction involving the reaction of anthranilic acid with a phosgene or phosgene equivalent. For literature important to this method, see Coppola, Synthesis 1980, 505 and Fabis et al., Tetrahedron, 1998, 10789.

Synthesis of isatonic anhydride of formula 27 can also be accomplished from isatin of formula 30 as shown in Scheme 12 below.

Isatin of Formula 30 is described, for example, in F. D. Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58 and [J. F. M. Da Silva et al., Journal of the Brazilian Chemical Society 2001, 12 (3), 273-324, obtainable from aniline derivatives of formula 29. In general, oxidizing isatin 30 with hydrogen peroxide yields the corresponding isotonic acid anhydride 28 in good yield (G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19, 222- 223]).

As shown in Scheme 13, isatin of Formula 30 wherein R ² is Cl, Br or I is also obtainable from 5-unsubstituted isatin of Formula 31 by halogenation. The cyanide substitution may then provide isatin of Formula 30a (Formula 30 wherein R ² is CN).

Halogenation reactions can be carried out using many reagents and procedures known in the literature. Suitable reagents include elemental halogens (chlorine, bromine, or iodine), "positive-halogen" reagents such as trichloroisocyanuric acid, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS), and mixtures comprising halogenation reagents such as hydrogen peroxide and hydrogen halides. Halogen at the 5-position of isatin of Formula 30 wherein R ² is Cl, Br or I can be substituted with cyanide using methods known in the literature. This method usually involves the use of cyanide salts with metal compounds, usually in the presence of a ligand such as substituted phosphine or substituted bisphosphinoalkanes. Suitable methods are described in PE Maligres et al., Tetrahedron Letters 1999, 40, 8193-8195, and in M. Beller et al., Chem. Eur. J. 2003, 9 (8), 1828-1836, using a palladium compound as described in SL Buchwald in J. Am. Chem. Soc. 2003, 125, 2890-2891, and methods of using copper compounds and European Patent No. 384392, and K. Sasaki in Bull. Chem. Soc. Japan 2004, 77, 1013-1019, and RK Arvela and NE Leadbeater in J. Org. Chem. 2003, 68, 9122-9125, and methods for using nickel compounds. Those skilled in the art will appreciate that when R ¹ is Cl, it is preferred that R ² in Formula 30 is Br or I in order to obtain selectivity in cyanation (ie substitution of halogen by cyanide).

As shown in Scheme 14 below, the anthranylamides of formula 3 are typically reacted with the corresponding hydrogenated compounds of formula 32 through catalyzed hydrogenation of nitro groups followed by reaction of the anthranilic acid esters of formula 33 with ammonia or alkylamines. Obtainable from nitrobenzoic acid (or ester).

Typical reduction procedures involve the reduction to hydrogen in hydroxyl solvents such as ethanol and isopropanol in the presence of a metal catalyst such as palladium or platinum oxide on carbon. Reduction can also be carried out in the presence of zinc in acetic acid. These methods for reducing nitro groups are well documented in the chemical literature. Many methods for the interconversion of carboxylic acids, esters, and amides are also well documented in the chemical literature.

As shown in Scheme 15 below, the anthranylamides of formula 3 are also obtainable from halogenated 5-unsubstituted anthranylamides of formula 34, which is an anthranyl of formula 3 wherein R ² is Br, Cl or I Amide is then provided, optionally by cyanide substitution, to provide anthranilamide of Formula 3a (Formula 3 wherein R ² is CN).

Suitable methods and procedures are similar to those described for the halogenation and cyanide substitutions known in the literature and shown in Scheme 13. Those skilled in the art will appreciate that halogenation and cyanation may also be carried out in other steps in the preparation of the anthranylamides of formula (3).

It will be appreciated that some of the reagents and reaction conditions described above for preparing compounds of Formula 2 and compounds of Formula 3 may not be compatible with the specific functional groups present in the intermediate. In this case, adding a protective / deprotective sequence or functional interconversion to the synthesis will assist in obtaining the desired product. The use and selection of protecting groups will be apparent to those skilled in chemical synthesis (see, e.g., Greene, T. W., Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed., Wiley, New York, 1991). Those skilled in the art will, in some cases, need to perform additional routine synthetic steps that are not described in detail after introduction of a given reagent when shown in any individual scheme to complete the synthesis of the compound of Formula 2 and the compound of Formula 3 It will be appreciated. Those skilled in the art will appreciate that it may be necessary to carry out the combination of steps described in the above schemes in an order other than those implied in the particular order provided for the preparation of the compounds of formula (2) and compounds of formula (3). Those skilled in the art will also appreciate that compounds of formula (2) and compounds of formula (3) and intermediates described herein are subjected to various electrophilic reactions, nucleophilic reactions, radical reactions, organometallic reactions, oxidation reactions, and reduction reactions to which substituents are added or present. It will be appreciated that substituents may be modified.

Without further effort, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest. The following examples are, therefore, to be construed as illustrative only and are not intended to limit the invention in any case. The steps of the following examples describe the procedures for each step in the overall synthetic transformation, and the starting material of each step may not necessarily be prepared by the specific preliminary procedure described in other examples or steps. Percentages are by weight except for chromatographic solvent mixtures or unless otherwise indicated. Parts and percentages for chromatographic solvent mixtures are based on volume unless otherwise indicated. ¹ H NMR spectra were reported in ppm downfield from tetramethylsilane, where s is singlet, d is doublet, t is triplet, q is quadruple, m is multiplet, dd is doublet, dt Is a triplet of triplets, br s is a broad singlet. Ace C18 or C4 Ultra Inert® Chromatography Columns (Reverse Phase Columns manufactured by MacMod Analytical Inc., Chad Ford, 19317, PA) (particle size) Quantitative HPLC of the product was performed using 3 μm, 4.6 mm × 15 cm, eluent 5 to 80% acetonitrile / pH 3 phosphate buffer).

Example 1

2-Amino-5- Chloro -N, 3- Of dimethylbenzamide  Produce

Acetic acid (7.3 g, 122 mmol) in a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione (211.6 g, 1000 mmol) in acetonitrile (700 mL) Was added. 40% aqueous methylamine (104 mL) was then added dropwise at 25-30 ° C. over 30 minutes. Stirring was continued for 2 hours, then water (700 mL) was added slowly. The resulting suspension was cooled to 5 ° C. and stirred at this temperature for 30 minutes. The suspension was then filtered, the solid was washed with water (3 x 200 mL) and dried under nitrogen to yield the title compound as an off-white needle (172.8 g (87.0% yield)).

Example 2

Preparation of Methyl 2-amino-5-chloro-3-methylbenzoate

Step A: 2-Amino-5- Chloro -3- Methylbenzoic acid  Produce

N-chlorosuccinimide (13.3 g, 99.2 mmol) is added to a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N, N-dimethylformamide (50 mL). And the reaction mixture was heated to 100 ° C. for 30 minutes. The heater was removed and the reaction mixture was cooled to room temperature and left overnight. The reaction mixture was then poured slowly into ice water (250 mL) to precipitate a white solid. The solid was filtered off, washed four times with water and taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried (MgSO ₄ ), evaporated under reduced pressure, and the residual solid washed with ether to yield the desired intermediate as a white solid (13.9 g (75.4% yield)).

Step B: methyl  2-Amino-5- Chloro -3- Methylbenzoate  Produce

 1,4-diaza-ratio in a suspension of 2-amino-5-chloro-3-methylbenzoic acid (ie, the product of Step A) (92.8 g, 500 mmol) in acetonitrile (500 mL) at 0-5 ° C. Cyclo [5.4.0] undec-7-ene (DBU, 90 mL, 92 g, 600 mmol) was added and then dimethyl sulfate (57 mL, 76 g, 600 mmol) was added dropwise at 0-5 ° C. . After stirring for 3 hours at this temperature, additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After 3 hours more stirring at this temperature, additional DBU (15 mL) and dimethyl sulphate (10 mL) were added. After 2 hours more stirring at this temperature, concentrated hydrochloric acid (60 mL, 720 mmol) was added dropwise at 0-10 ° C. The resulting suspension was stirred for 30 minutes at 0-5 ° C., then filtered and the solid was washed with ice cooled 2: 1 water-acetonitrile (3 × 100 mL) and dried under nitrogen. The crude product was suspended in methanol (250 mL), water (1000 mL) was added and the mixture was stirred at rt for 1 h. The solid was then filtered off, washed with 4: 1 water-methanol (100 mL), followed by water (3 × 100 mL) and dried under nitrogen to yield the title compound as a low melting white solid (87.6 g (yield 87.8). %)). HPLC of the solid product showed that the title ester was present at 99.7 area%.

Example 3

2-Amino-5- Chloro -N, 3- Of dimethylbenzamide  Produce

Methylamine in ethylene glycol (12.4 g) in a suspension of methyl 2-amino-5-chloro-3-methylbenzoate (ie the product of Example 2) (4.03 g, 20.2 mmol) in acetonitrile (12.4 g) ( 3.1 g, 0.10 mol) of solution was added. The mixture was heated at 60 ° C. for 23 hours and then cooled to room temperature. Water (25 mL) was added dropwise and the resulting slurry was cooled to 5 ° C. and stirred at this temperature for 10 minutes. The mixture was filtered and the solid washed with water (3 × 10 mL) and dried under nitrogen to yield the title compound as a white needle (3.43 g (85.5% yield)).

Example 4

Preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide

Step A: methyl  2-amino-3- Methylbenzoate  Produce

600-mL of methyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5% Pd / C (Degussa CE 105 XRC / W, 1.0 g), and acetonitrile (300 mL) Compounded in pressure vessel. The mixture was heated to 70 ° C. and hydrogenated at 65 psi (450 kPa) for 8 hours. Additional 5% Pd / C (1.0 g) was added and hydrogenation continued at 100 psi (690 kPa) for 8.5 hours. The reaction mixture was then cooled, purged with nitrogen, filtered through a Celite® diatom filter aid and rinsed with acetonitrile (3 x 25 mL). The combined filtrates were partially evaporated to a weight of about 160 g and then diluted with acetonitrile to a total weight of 200 g. Quantitative HPLC of this solution showed the title compound was present at 40.3% by weight (80.6 g, yield 97.5%).

Step B: methyl  2-Amino-5- Chloro -3- Methylbenzoate  Produce

The solution prepared in step A (195 g, 475 mmol) was diluted with acetonitrile (50 mL) and heated to 50 ° C. Then a solution of sulfuryl chloride (70.6 g, 523 mmol) in acetonitrile (100 mL) was added at 50-55 ° C. over 3.25 h. Immediately after the addition was complete, the mixture was cooled to 5 ° C., water (150 g) was added, and 50% aqueous sodium hydroxide (103 g) was added slowly to adjust the pH of the solution to 6.0. After stirring for 10 min at this temperature, the organic layer was separated and the aqueous layer was extracted with acetonitrile (50 mL). The organic layers were combined, dried (MgSO ₄ ) and partially evaporated to a weight of 193.7 g. Quantitative HPLC of this solution showed the title compound was present at 41.5% by weight (80.4 g, yield 84.8%).

Step C: 2-Amino-5- Chloro -N, 3- Of dimethylbenzamide  Produce

The solution prepared in step B (96.2 g, 200 mmol) was diluted with acetonitrile (60.0 g) and ethylene glycol (180 g) and azeotropically dried by distillation at atmospheric pressure under a Claisen distillation head to about 72 mL of volatiles was removed. The distillation head was then replaced with a dry-ice-cooled condenser, the residual solution was cooled to 0-5 ° C., and methylamine gas (31.1 g, 1000 mmol) was lowered below the surface of the reaction mixture. Added. The mixture was heated at 70 ° C. for 17.5 h, then water (400 mL) was added slowly to precipitate the product. The mixture was cooled slowly to 5 ° C., stirred at this temperature for 15 minutes, filtered and the solid washed with water and dried under nitrogen to yield the desired compound (36.36 g, 91.5% yield). HPLC showed that the purity was 99.3 area%.

Example 5

Preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide

Step A: 2-amino-N, 3- Of dimethylbenzamide  Produce

8-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione (PCT Patent Publication WO 00/27831) (18 g, 0.1 mol) and acetic acid (1.2 in ethyl acetate (200 mL) g, 0.02 mol) was warmed to 35 ° C. and aqueous methylamine (40%, 9.0 g, 0.12 mol) was added dropwise at 35-37 ° C. over 50 minutes. Then additional aqueous methylamine (40%, 0.9 g, 12 mmol) was added and the mixture was stirred at 36 ° C. for an additional 2.5 hours. Water (20 mL) was then added, the layers separated and the organic layer washed with water, dried (MgSO ₄ ) and evaporated to yield the title compound (15.45 g (92%)).

Step B: 2-Amino-5- Chloro -N, 3- Of dimethylbenzamide  Produce

 A mixture of 2-amino-N, 3-dimethylbenzamide (ie, the product of Step A) (16.6 g, 100 mmol) and N, N-dimethylformamide (15.0 g) was cooled to 10 ° C. and concentrated hydrochloric acid ( 70 g, 700 mmol) was added slowly. The mixture was then heated to 30 ° C. and 30% aqueous hydrogen peroxide (18.5 g, 160 mmol) was added dropwise at 30-35 ° C. over 15 minutes. After stirring at about 35 ° C. for 3 hours, the mixture was cooled to about 10 ° C. and then water (200 mL) was added. After addition of sodium sulfite (7.56 g, 60 mmol), the pH was adjusted to 2.2 by slowly adding 50% aqueous sodium hydroxide (38.1 g). After stirring at 10 ° C. for 15 minutes, the mixture is filtered, the solid is washed with water (2 × 50 mL) and dried in a vacuum oven to yield the title compound as a pink solid (14.61 g (72.7% yield)). . Quantitative HPLC of the solid product showed 99.1 wt% of the title compound.

Example 6

Preparation of 2-amino-5-cyano-N, 3-dimethylbenzamide

Step A: 2-Amino-5- Bromo -N, 3- Of dimethylbenzamide  Produce

A mixture of 2-amino-N, 3-dimethylbenzamide (ie, the product of Step A of Example 5) (14 g, 85 mmol), acetic acid (50 mL), and water (50 mL) was cooled to 12 ° C. Concentrated hydrobromic acid (28.5 g, 0.34 mol) was added at this temperature over 10 minutes. 30% aqueous hydrogen peroxide (9 g, 0.08 mol) was then added at 10-11 ° C. over 5 minutes and the mixture was slowly warmed to room temperature with stirring for 2.5 hours. Then additional concentrated hydrobromic acid (2.9 g) was added and the mixture was stirred at rt overnight. To the mixture was then added water (50 mL), sodium bisulfite (1.5 g), and then the pH was adjusted to 5-6 by addition of 50% aqueous sodium hydroxide (about 15 mL). The mixture was filtered, the solid was washed with water and dried in vacuo to yield the title compound (19.5 g (94%)).

Step B: 2-Amino-5- Cyano -N, 3- Of dimethylbenzamide  Produce

Palladium (II) acetate (370 mg, 1.64 mmol), 1,4-bis (diphenylphosphino) butane (850 mg, 2 mmol), activated zinc powder (500 mg, 7.64 mmol) in a flask purged with anhydrous nitrogen , Zinc cyanide (II) (51 g, 434 mmol), and 2-amino-5-bromo-N, 3-dimethylbenzamide (ie, the product of Step A) (200 g, 820 mmol) were charged. Freshly degassed N, N-dimethylformamide (500 mL) was then added and the mixture was heated at 130 ° C. for 25.5 h. The temperature was then lowered to 95 ° C. and acetic acid (200 mL) was added. Hydrogen cyanide was removed through a scrubber filled with aqueous sodium hydroxide and sodium hypochlorite solution by sparging nitrogen with the mixture while cooling to room temperature. Water (1500 mL) was then added over 1.5 hours and nitrogen sparging continued overnight. The mixture was then filtered, the solid was washed with water and dried in a vacuum oven to yield the title compound as a downy pale yellow solid (141.5 g (yield 90.9%)).

Example 7

3- Bromo -N- [4- Chloro -2- methyl -6-[( Methylamino ) Carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (35 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) (Purity 93.6%, 16.16 g, 50.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie the product of Examples 1, 3, 4 and 5) (10.43 g, 52.5 mmol) 3-picoline (12.65 mL, 12.11 g, 130 mmol) was added to the mixture. After the mixture was cooled to -5 ° C, a solution of methanesulfonyl chloride (4.64 mL, 6.89 g, 60 mmol) in acetonitrile (10 mL) was added dropwise at -5 to 0 ° C. The mixture was stirred at this temperature for 15 minutes and then at room temperature for 3 hours. Water (15 mL) was then added dropwise and the mixture was cooled to 0 ° C. for 1 hour. The mixture was filtered and the solid was washed with 3: 1 acetonitrile-water (2 x 10 mL) and then with acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as a light brown powder (23.98 g (Incorrect yield 92.9%)). m.p. 239 to 240 ° C.

Example 8

3- using pyridine as base Bromo -N- [4- Chloro -2- methyl -6-[( Methylamino ) Carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) (6.05 g, 20.0 mmol) and pyridine in a mixture of 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, the products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) 4.20 mL, 4.11 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at this temperature for 1 hour and then at room temperature for 3 hours. Water (6 mL) was then added dropwise and the mixture was stirred at rt for 1 h. The mixture was filtered and the solid was washed with 3: 1 acetonitrile-water (2 x 4 mL) and then with acetonitrile (2 x 4 mL) and dried under nitrogen to yield the title compound as an off-white powder (9.35 g (Incorrect yield 96.8%)).

Example 9

3- using "mixed picoline" as base Bromo -N- [4- Chloro -2- methyl -6-[(methylamino) carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3- in a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (2.53 mL, 2.42 g, 26 mmol) was added followed by 4-picoline (2.53 mL, 2.42 g, 26 mmol). After adding 4-picoline, the mixture became very thick. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 2 hours. Water (6 mL) was then added dropwise and the mixture was stirred at 0 ° C. for 1 hour. The mixture was filtered and the solid was washed with 3: 1 acetonitrile-water (2 x 4 mL) and then with acetonitrile (2 x 4 mL) and dried under nitrogen to yield the title compound as a yellow powder (9.15 g (Incorrect yield 94.7%)).

Example 10

3- in acetone Bromo -N- [4- Chloro -2- methyl -6-[(methylamino) carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetone (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) ( 6.05 g, 20.0 mmol) and 3-pi in a mixture of 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, the products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Choline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at 0 ° C for 1 h. The mixture was filtered and the solid was washed with ice cold 2: 1 acetone-water (2 × 4 mL) and dried under nitrogen to yield the title compound as an almost white powder (9.32 g (incorrect yield 96.4%)). ).

Example 11

3- in tetrahydrofuran Bromo -N- [4- Chloro -2- methyl -6-[( Methylamino ) Carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in tetrahydrofuran (THF, 18 mL) (PCT Patent Publication WO 03/015519 for the preparation) 3) to a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at 0 ° C for 1 h. The mixture was filtered and the solid washed with ice cold 2: 1 THF-water (2 × 4 mL) and dried under nitrogen to yield the title compound as an almost white powder (6.93 g (incorrect yield 71.7%)). ).

Example 12

3- in dichloromethane Bromo -N- [4- Chloro -2- methyl -6-[( Methylamino ) Carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in dichloromethane (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3- in a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie, the products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Then water (9 mL) was added dropwise. Additional dichloromethane (18 mL) was added to stir the thick suspension and the mixture was stirred at 0 ° C. for 1 h. The mixture was filtered and the solid washed with ice cold 2: 1 dichloromethane-water (2 x 4.5 mL) and dried under nitrogen to yield the title compound as an almost white powder (8.86 g (incorrect yield 91.7%). )).

Example 13

Propionitrile  3-of Bromo -N- [4- Chloro -2- methyl -6-[( Methylamino ) Carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in propionitrile (18 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) ) In a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (ie the product of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 1 hour and then at room temperature for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at rt for 1 h. The mixture is filtered and the solid is washed with 3: 1 propionitrile-water (2 x 4 mL) followed by propionitrile (2 x 4 mL) and dried under nitrogen to yield the title compound as an almost white powder. (9.37 g (incorrect yield 97.0%)).

Example 14

methyl  3- in ethyl ketone Bromo -N- [4- Chloro -2- methyl -6-[( Methylamino ) Carbonyl] Phenyl ] -1- (3- Chloro -2- Pyridinyl ) -1H- Pyrazole -5- Carboxamide  Produce

3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in methyl ethyl ketone (MEK, 18 mL) (PCT Patent Publication WO 03/015519 for the preparation) 3) to a mixture of (6.05 g, 20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (products of Examples 1, 3, 4 and 5) (4.17 g, 21.0 mmol) Picoline (5.06 mL, 4.84 g, 52 mmol) was added. After the mixture was cooled to -5 ° C, methanesulfonyl chloride (1.86 mL, 2.75 g, 24 mmol) was added dropwise at -5 to 0 ° C. The mixture was stirred at 0-5 ° C. for 3 hours. Water (9 mL) was then added dropwise and the mixture was stirred at rt for 1 h. The mixture was filtered, the solid was washed with 3: 1 MEK-water (2 × 4 mL), then MEK (2 × 4 mL) and dried under nitrogen to yield the title compound as an almost white powder (9.27 g). (Incorrect yield 95.9%)).

Example 15

3- Bromo -1- (3- Chloro -2- Pyridinyl ) -N- [4- Cyano -2- methyl -6-[( Methylamino ) -Carbonyl] Phenyl ] -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3-p into a mixture of (purity 95.4%, 15.85 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie, the product of Example 6) (9.93 g, 52.5 mmol) Choline (17.5 mL, 16.7 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 3 hours. Water (55 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred at 0-5 ° C. for 1 hour. The mixture was then filtered and the solid was washed with 2: 1 acetonitrile-water (2 x 10 mL), then with acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (24.70). g (incorrect yield 99.5%)). m.p. 177-181 ° C. (decomposed).

Crude product (5.00 g) was crystallized from 1-propanol (50 mL) to yield the title compound as white crystals (4.44 g (88.8% recovery)). m.p. 217-219 ℃

Example 16

3- using pyridine as base Bromo -1- (3- Chloro -2- Pyridinyl ) -N- [4- Cyano -2- methyl -6-[( Methylamino ) -Carbonyl] Phenyl ] -1H- Pyrazole -5- Carboxamide  Produce

 3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) Pyridine (14.6 mL, in a mixture of 95.4% purity, 15.85 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (product of Example 6) (9.93 g, 52.5 mmol) 14.3 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 3 hours. The mixture was then warmed to rt and water (85 mL) was added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred for 1 hour. The mixture was then filtered, the solid was washed with 4: 3 acetonitrile-water (2 x 10 mL), then acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (24.29 g (Incorrect yield 97.9%)).

Example 17

3- using 2-picolin as base Bromo -1- (3- Chloro -2- Pyridinyl ) -N- [4-cyano-2- methyl -6-[( Methylamino ) -Carbonyl] Phenyl ] -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 2-ply in a mixture of (purity 96.7%, 15.64 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie, the product of Example 6) (9.93 g, 52.5 mmol) Choline (17.8 mL, 16.8 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes, then at 0-5 ° C. for 3 hours, then at room temperature for 18 hours. Water (25 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred for 1 hour. The mixture was then filtered and the solid was washed with 4: 1 acetonitrile-water (2 x 10 mL), then acetonitrile (2 x 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (22.52 g (Inaccurate yield 92.0%)).

Example 18

2,6- as base Lutidine  3- used Bromo -1- (3- Chloro -2- Pyridinyl ) -N- [4- Cyano -2- methyl -6-[( Methylamino ) -Carbonyl] Phenyl ] -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetonitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 2,6 in a mixture of (purity 97.6%, 15.50 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie the product of Example 6) (9.93 g, 52.5 mmol) -Lutidine (21.0 mL, 19.3 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes, then at 0-5 ° C. for 1 hour and then at room temperature for 1 hour. NMR analysis of the reaction showed little to no title compound, but 10.3% of the cyclized derivative was formed. Additional 2,6-lutidine (11.7 mL, 10.8 g, 100 mmol) and methanesulfonyl chloride (3.9 mL, 5.8 g, 50 mmol) were added and the mixture was stirred at rt for 22 h. Analysis of the reactants indicated that 9.6% of the title compound and 89.8% of cyclized derivatives were formed. Water (55 mL) was added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred for 1 hour. The mixture was then filtered, the solid was washed with 2: 1 acetonitrile-water (2 x 10 mL) and then with acetonitrile (2 x 10 mL) and dried under nitrogen to yield a light yellow powder (21.92 g ). This solid was suspended in acetonitrile (60 mL), water (10 mL) and hydrochloric acid (1 N, 10 mL) were added and the mixture was stirred at rt for 30 min. The mixture was then filtered, the solid was washed with 3: 1 acetonitrile-water (2 x 10 mL) and then with acetonitrile (2 x 10 mL) and dried in a vacuum oven to yield the title compound as an off-white powder ( 20.72 g (incorrect yield 85.4%)).

Example 19

3- in acetone Bromo -1- (3- Chloro -2- Pyridinyl ) -N- [4- Cyano -2- methyl -6-[(methylamino) -carbonyl] Phenyl ] -1H- Pyrazole -5- Carboxamide  Produce

3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in acetone (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) ( 3-picoline in a mixture of 97.6% purity, 15.50 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (ie, the product of Example 6) (9.93 g, 52.5 mmol) (17.5 mL, 16.7 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 3 hours. Water (55 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred at 0-5 ° C. for 1 hour. The mixture was then filtered and the solid was washed with 2: 1 acetone-water (3 × 10 mL) and dried under nitrogen to yield the title compound as an off-white powder (24.07 g (incorrect yield 99.2%)). Karl Fisher titration (KFT) of this solid showed that it contained 5.5% by weight of water. A portion of the solid (23.35 g) was dried in a vacuum oven to yield the title compound as an off-white powder (22.16 g, containing 0.76 wt.% Water as measured by KFT).

Example 20

Propionitrile  3-of Bromo -1- (3- Chloro -2- Pyridinyl ) -N- [4- Cyano -2-methyl-6-[( Methylamino ) -Carbonyl] Phenyl ] -1H- Pyrazole -5- Carboxamide  Produce

3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid in propionitrile (120 mL) (see PCT Patent Publication No. WO 03/015519 for preparation) 3-picoline in a mixture of) (purity 97.6%, 15.50 g, 50.0 mmol) and 2-amino-5-cyano-N, 3-dimethylbenzamide (product of Example 6) (9.93 g, 52.5 mmol) (17.5 mL, 16.7 g, 180 mmol) was added. After the mixture was cooled to -10 ° C, a solution of methanesulfonyl chloride (5.4 mL, 8.0 g, 70 mmol) was added dropwise at -10 to -5 ° C. The mixture was stirred at this temperature for 5 minutes and then at 0-5 ° C. for 4 hours. Water (55 mL) was then added dropwise. The mixture was stirred for 15 minutes, then concentrated hydrochloric acid (5.0 mL, 60 mmol) was added dropwise and the mixture was stirred at 0-5 ° C. for 1 hour. The mixture was then filtered and the solid was washed with 2: 1 propionitrile-water (2 × 10 mL) followed by propionitrile (2 × 10 mL) and dried under nitrogen to yield the title compound as an off-white solid. (21.85 g (incorrect yield 90.1%)). The Karl Fischer titration (KFT) of this solid showed that it contained 5.4% by weight of water. A portion of the solid (21.03 g) was dried in a vacuum oven to yield the title compound as off-white powder (20.07 g, containing 0.9 wt.% Water as measured by KFT).

The following abbreviations are used in the table below.

t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, , i -Pr means isopropyl, Bu means butyl. By the procedures described herein together with methods known in the art, the compounds of Table 1 can be prepared and used in the methods of the present invention.

Table 2 illustrates certain conversions for preparing compounds of Formula 1 according to the methods of the present invention.

Claims (12)

Preparation of a compound of formula (1) comprising combining (1) a carboxylic acid compound of formula (2), (2) aniline compound of formula (3), and (3) sulfonyl chloride to form a compound of formula (1) Way. &Lt; Formula 1 >

<Formula 2>

<Formula 3>

Wherein, R ¹ is CH ₃ or Cl, R ² is Br, Cl, I or CN, R ³ is H or C ₁ -C ₄ alkyl, R ⁴ is Cl, Br, CF ₃ , OCF ₂ H or OCH ₂ CF ₃ , R ⁵ is F, Cl or Br, R ⁶ is H, F or Cl, Z is CR ⁷ or N, R ⁷ is H, F, Cl or Br. The method of claim 1, wherein the sulfonyl chloride is of formula 4. &Lt; Formula 4 > R ⁸ S (O) ₂ Cl Wherein R ⁸ is C ₁ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, or phenyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl and nitro to be. The method of claim 2, wherein the sulfonyl chloride is methanesulfonyl chloride. The method of claim 1, wherein the carboxylic acid of formula 2 is combined with aniline of formula 3 to form a mixture, and then the mixture is combined with sulfonyl chloride. The method of claim 4, wherein the base is combined with a compound of Formula 2 and a compound of Formula 3 to form a mixture before combining with sulfonyl chloride. The method of claim 5 wherein the base is selected from tertiary amines. The method of claim 6, wherein the base is selected from substituted or unsubstituted pyridine. 8. The method of claim 7, wherein the base is selected from 2-picoline, 3-picoline, 2,6-lutidine and pyridine. The method of claim 8, wherein the sulfonyl chloride is of formula 4. &Lt; Formula 4 > R ⁸ S (O) ₂ Cl Wherein R ⁸ is C ₁ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, or phenyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl and nitro to be. The process according to claim 1 or 4, wherein the solvent is combined with the compound of formula 2, the compound of formula 3 and sulfonyl chloride. The method of claim 10, wherein the solvent is acetonitrile. A compound of formula <Formula 3>

Wherein, R ¹ is CH ₃ or Cl, R ² is Br, Cl, I or CN, R ³ is H or C ₁ -C ₄ alkyl, (a) when R ¹ and R ² are Cl, R ³ is other than H, CH ₂ CH ₃ or CH (CH ₃ ) CH ₂ CH ₃ ; (b) when R ¹ is CH ₃ and R ² is Cl, Br or CN, R ³ is other than CH ₃ or CH (CH ₃ ) ₂ , (c) when R ¹ is Cl and R ² is Cl or Br, R ³ is other than CH ₃ or CH (CH ₃ ) ₂ , (d) When R ¹ is CH ₃ and R ² is CN, R ³ is other than H.